The existence of neurotransmitter receptor heteromers is becoming broadly accepted and their functional significance is being revealed. Heteromerization of neurotransmitter receptors produces functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. We have recently hypothesized that neurotransmitter receptor heteromers can function as processors of computation that modulate cell signaling (1). Thus, the quantitative and qualitative aspects of the signaling generated by stimulation of any of the individual receptor units in the heteromer are different from those obtained during coactivation. Some neurotransmitter heteromers can exert an effect as processors of computations that directly modulate pre- or postsynaptic neurotransmission (1). We have also hypothesized that some neurotransmitter heteromers play a key integrative role in local modules (2), which we have defined as a minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit (2). Our recent work is related to the identification and study of the neurotransmitter receptor heteromers that modulate the function of the striatal spine module, which is the most common local module in the striatum (2). The striatal spine module is comprised of the dendritic spine of the medium spiny neuron, its glutamatergic and dopaminergic terminals and astroglial processes. We believe that understanding the integrated function of the striatal spine module will have important implications for the study of basal ganglia function and disfunction, including drug abuse.[unreadable] [unreadable] The main neurotransmitters influencing the striatal spine module are dopamine, glutamate, adenosine, acetylcholine, endocannabinoids, serotonin and histamine. In previous studies we discovered the existence of heteromerization between the following receptors localized in different elements of the striatal spine module: adenosine A2A and dopamine D2, adenosine A1 and dopamine D1, adenosine A1 and adenosine A2A, adenosine A2A and metabotropic glutamate mGlu5 and dopamine D2 and nicotinic acetyl-choline (alpha4-beta2) (1-9). During the last year we demonstrated the existence of adenosine A2A-cannabinoid CB1 receptor (10). A2A and CB1 receptors were found to coimmunoprecipitate from extracts of rat striatum, where they colocalize in dendritic processes and possibly nerve terminals (10). At a functional level we found that, in this heteromer, CB1 receptor does not couple to Gi proteins unless there is coactivation of A2A receptors. Thus CB1 receptor function in the heteromer depends on A2A receptor activation (10). In fact, the motor depressant effects of centrally administered CB1 receptor agonist were completely counteracted by an A2A receptor antagonist (11). This suggests that the reinforcing effects of cannabinoids might also depend on striatal A2A-CB1 receptor heteromers. In fact, we have obtained preliminary evidence indicating that A2A receptor antagonists can counteract self-administration of THC or the encocannabinoid anandamide in squirrel monkeys.[unreadable] [unreadable] By combining in vivo microdialysis and in vitro synaptosomal techniques, we have found very important regional differences in the adenosine-mediated regulation of the striatal spine function (11). Thus, we found a differential glutamate-dependent and glutamate-independent adenosine A1 receptor-mediated modulation of dopamine release in different striatal compartments. The glutamate-dependent mechanism is mediated by the A1-A2A receptor heteromers localized in glutamatergic terminals and NMDA receptors localized in dopaminergic terminals (11). Furthermore, we were able to establish, for the first time, the existence of functional inhibitory A1 receptors in the striatal dopaminergic terminals (11). Those receptors are involved in the glutamate-independent mechanism. These results emphasize the care required when drawing general conclusions on the role of a particular neuromodulatory system in a particular brain area when only a limited set of local modules are studied. These studies also shed light on the central mechanisms of action of caffeine.[unreadable] [unreadable] Finally, during the last year we have studied pharmacological interactions between the psychostimulants methamphetamine and methylphenidate, by using motor activity recording and in vivo microdialysis techniques. These experiments led to the discovery of a potent serotoninergic modulation of methylphenidate-induced locomotor activation in rats, which selectively involved serotonin 5-HT1B receptors (12). A selective 5-HT1B receptor agonist strongly and potently potentiated methylphenidate-induced locomotor activation (12). These results can have implications for the treatment of attention-deficit hyperactivity disorder.